The purpose of this project is to identify age-related changes in thermoregulation in mice, and analyze physiological mechanisms underlying these changes. We have reported previously that, compared with adult mice, the ability of aged mice to retain core body temperature during exposure to cold is compromised and that, unlike adults, cold tolerance of aged mice does not improve with repeated exposure to cold. Recent studies have shown that the deficit in thermoregulation involves age-associated changes in skeletal muscle, while mechanisms of nonshivering thermogenesis remain equivalent to or greater than those of adults. One series of experiments showed that cold-induced expression of uncoupling protein in brown adipose tissue (BAT) in aged mice was comparable to that of adults, while another indicated that peripheral vasoconstriction to cold was greater in aged than in adult mice (including even the mild cold of normal room temperature). A study of the effects of repeated cold exposure showed that those animals whose cold tolerance improved were characterized by increases in sympathetic outflow to BAT and in metabolic heat production, while others who showed no increase in cold tolerance showed no such effects, and were not different from control animals with no history of cold exposure. Nevertheless, synthesis of uncoupling protein in BAT was increased whether or not cold tolerance improved. These studies indicate that increased expression of uncoupling protein in BAT is necessary, but not sufficient, for cold acclimation, which also requires increases in sympathetic nervous system activity. Finally, it was shown that six weeks of daily treadmill exercise training in cold improved cold tolerance in aged, but not in adult mice, confirming the view that deficits in cold tolerance in aged animals is associated with declining contribution of skeletal muscle to heat production.